The sugars attached to pharmaceutically important natural products often dictate key pharmacological properties and/or molecular mechanisms of action. While there is precedent for improving non-glycosylated natural product-based therapeutics via glycoconjugation with, among others, colchicine, mitomycin, podophyllotoxin, rapamycin, or taxol, studies designed to systematically understand and/or exploit the role of carbohydrates in drug discovery are often limited by the availability of practical synthetic and/or biosynthetic tools.
Among the contemporary options to address this limitation, neoglycosylation takes advantage of a chemoselective reaction between free reducing sugars and Nmethoxyamino-substituted acceptors. This reaction has enabled the process of ‘neoglycorandomization’ wherein alkoxyamine-appended natural product-based drugs are differentially glycosylated with a wide array of natural and unnatural reducing sugars.
Neoglycorandomization has led to increases in anticancer efficacy of the cardenolide digitoxin, mechanistic alteration and improvements in the synergistic effects of the non-glycosylated alkaloid colchicine, and enhancements in the potency of the glycopeptide vancomycin against antibiotic resistant organisms. Importantly, although many natural products are known to exhibit multiple, diverse biological activities, neoglycorandomization to date has focused upon natural product-based drugs with predominately singular, distinct mechanisms of action.
Cancer affects approximately 20 million adults and children worldwide, with more than 9 million new cases diagnosed annually (International Agency for Research on Cancer). According to the American Cancer Society, about 563,100 Americans are expected to die of cancer this year, more than 1500 people a day. Since 1990, in the United States alone, nearly five million lives have been lost to cancer, and approximately 12 million new cases have been diagnosed.
Currently, cancer therapy involves surgery, chemotherapy and/or radiation treatment to eradicate neoplastic cells in a patient (see, for example, Stockdale, 1998, “Principles of Cancer Patient Management”, in Scientific American: Medicine, vol. 3, Rubenstein and Federman, eds., Chapter 12, Section 9). All of these approaches pose significant drawbacks for the patient. Surgery, for example, may be contraindicated due to the health of the patient or may be unacceptable to the patient. Additionally, surgery may not completely remove the neoplastic tissue. Radiation therapy is effective only when the irradiated neoplastic tissue exhibits a higher sensitivity to radiation than normal tissue, and radiation therapy can also often elicit serious side effects.
With respect to chemotherapy, there are a variety of chemotherapeutic agents available for treatment of neoplastic disease. However, despite the availability of a variety of chemotherapeutic agents, chemotherapy has many drawbacks (see, for example, Stockdale, 1998, “Principles of Cancer Patient Management” in Scientific American Medicine, vol. 3, Rubenstein and Federman, eds., ch. 12, sect. 10). Almost all chemotherapeutic agents are toxic, and chemotherapy causes significant, and often dangerous, side effects, including severe nausea, bone marrow depression, immunosuppression, etc. Additionally, many tumor cells are resistant or develop resistance to chemotherapeutic agents through multi-drug resistance.
Therefore, there exists a significant need in the art for novel compounds and compositions, and methods of preparing the same that are useful for treating cancer or neoplastic disease with reduced or without the aforementioned side effects. Further, there is a need for cancer treatments that provide cancer-cell-specific therapies with increased specificity and decreased toxicity.